Dosage forms containing apomorphine for ameliorating male erectile dysfunction

ABSTRACT

Psychogenic impotence or erectile dysfunction can be identified in psychogenic male patients and can be ameliorated, without substantial undesirable side effects, by sublingual administration of apomorphine dosage forms so as to maintain a plasma concentration of apomorphine of no more than about 5.5 nanograms per milliliter.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 09/102,235, filedJun. 22, 1998, now U.S. Pat. No. 5,985,889, which, in turn, is acontinuation of application Ser. No. 08/546,498, filed Oct. 20, 1995,now U.S. Pat. No. 5,770,606, which is a continuation-in-part ofapplication Ser. No. 08/231,250, filed Apr. 22, 1994, abandoned.

FIELD OF THE INVENTION

This invention, in one aspect, relates to dosage forms and methods forameliorating erectile dysfunction in psychogenic male patients. Inanother aspect this invention relates to diagnosis of erectiledysfunction. More particularly, this invention relates to the use ofapomorphine-containing compositions for amelioration of erectiledysfunction in psychogenic male patients and for diagnostic purposes.

BACKGROUND OF THE INVENTION

A normal erection occurs as a result of a coordinated vascular event inthe penis. This is usually triggered neurally and consists ofvasodilation and smooth muscle relaxation in the penis and its supplyingarterial vessels. Arterial inflow causes enlargement of the substance ofthe corpora cavernosa. Venous outflow is trapped by this enlargement,permitting sustained high blood pressures in the penis sufficient tocause rigidity. Muscles in the perineum also assist in creating andmaintaining penile rigidity. Erection may be induced centrally in thenervous system by sexual thoughts or fantasy, and is usually reinforcedlocally by reflex mechanisms. Erectile mechanics are substantiallysimilar in the female for the clitoris.

Impotence or male erectile dysfunction is defined as the inability toachieve and sustain an erection sufficient for intercourse. Impotence inany given case can result from psychological disturbances (psychogenic),from physiological abnormalities in general (organic), from neurologicaldisturbances (neurogenic), hormonal deficiencies (endocrine) or from acombination of the foregoing.

These descriptions are not exact, however. There is currently nostandardized method of diagnosis or treatment. As used herein,psychogenic impotence is defined as functional impotence with noapparent overwhelming organic basis. It may be characterized by anability to have an erection in response to some stimuli (e.g.,masturbation, spontaneous nocturnal, spontaneous early morning, videoerotica, etc.) but not others (e.g., partner or spousal attention).

Various methods for the treatment of impotence have been suggested,including external devices, for example, tourniquets (see U.S. Pat. No.2,818,855). In addition, penile implants, such as hinged or solid rodsand inflatable, spring driven or hydraulic models, have been used forsome time. The administration of erection effecting and enhancing drugsis taught in U.S. Pat. No. 4,127,118 to LaTorre. That patent teaches amethod of treating male impotence by injecting into the penis anappropriate vasodilator, in particular, an adrenergic blocking agent ora smooth muscle relaxant to effect and enhance an erection. Morerecently, U.S. Pat. No. 4,801,587 to Voss et al. teaches the applicationof an ointment to relieve impotence. The ointment consists of thevasodilators papaverine, hydralazine, sodium nitroprusside,phenoxybenzamine, or phentolamine and a carrier to assist absorption ofthe primary agent through the skin. U.S. Pat. No. 5,256,652 toEl-Rashidy teaches the use of an aqueous topical composition of avasodilator such as papaverine together withhydroxypropyl-β-cyclodextrin.

Recently the effect of apomorphine on penile tumescence in male patientsafflicted with psychogenic impotence has been studied. These studiesshow that while apomorphine can indeed induce an erection in apsychogenic male patient, the apomorphine dose required to achieve asignificant erectile response is usually accompanied by nausea or otherserious undesirable side effects such as hypertension, flushing anddiaphoresis. The specific mechanisms by which apomorphine acts toproduce an erectile response in a human patient are not yet completelyunderstood, however.

Moreover, apomorphine has been shown to have very poor oralbioavailability. See, for example, Baldessarini et al., in Gessa et al.,eds., Apomorphine and Other Dopaminomimetics, Basic Pharmacology, Vol.1, Raven Press, N.Y. (1981), pp. 219-228.

Thus the search is continuing for an effective treatment of psychogenicimpotence in male patients as well as for diagnostic methods that canidentify such patients. It has now been found that certain deliverysystems for apomorphine can provide a practical therapeutic and/ordiagnostic “window” while reducing the likelihood of undesirable sideeffects.

SUMMARY OF THE INVENTION

It has now been found that, for an optimal erectile response, steadystate circulating serum and mid-brain tissue levels of apomorphine areto be maintained within a relatively closely defined range.

Sublingual apomorphine dosage forms, usually containing about 2.5 toabout 10 milligrams of apomorphine, have been found to be effective inmale patients suffering from psychogenic erectile dysfunction for theinduction and maintenance of an erection sufficient for intercourse(i.e., vaginal penetration) without nausea or other undesirable sideeffects. The apomorphine is administered sublingually, preferably about15 to about 20 minutes prior to sexual activity, and so as to maintain apredetermined circulating serum levels and mid-brain tissue levels ofapomorphine during the period of sexual activity sufficient to induce anerection adequate for vaginal penetration but less than the amount thatinduces nausea. The plasma concentration of apomorphine should bemaintained at no more than about 5.5 nanograms per milliliter,preferably about 0.3 to about 4 nanograms per milliliter, and morepreferably about 1 to about 2 nanograms per milliliter.

The foregoing sublingual apomorphine dosage forms are also suitable forscreening patients complaining of erectile dysfunction so as to identifypatients of psychogenic etiology.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings,

FIG. 1 is a graphical representation of mean erectile function,expressed as RIGISCAN™ monitor value, as a function of apomorphine dose;

FIG. 2 is a bar graph depicting the percent successful erectile functionfor placebo, 3-milligram apomorphine dose, and 4-milligram apomorphinedose under erotic and neutral conditions;

FIG. 3 is a bar graph presenting yet another comparison of erectilefunction noted in Pilot Study #4 in terms of RIGISCAN™ monitor scoreversus placebo, 3 milligrams of apomorphine and 4 milligrams ofapomorphine under erotic and neutral conditions; and

FIG. 4 is a graphical representation of a comparison of the plasmaconcentration time profiles of apomorphine after intravenousadministration at a dose of 1 mg (open circles, n=7), sublingualadministration at a dose of 4 mg (open squares, n=4) and sublingualadministration at a dose of 8 mg (half-filled squares, n=4).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Apomorphine is a dopamine receptor agonist that has a recognized use asan emetic when administered subcutaneously in about a 5-milligram dose.For the purposes of the present invention, apomorphine or a similarlyacting dopamine receptor agonist is administered in an amount sufficientto excite cells in the mid-brain region of the patient but with minimalside effects. This cell excitation is believed to be part of a cascadeof stimulation that is likely to include neurotransmission withserotonin and oxytocin.

The dopamine receptors in the mid-brain region of a patient can bestimulated to a degree sufficient to cause an erection by the sublingualadministration of apomorphine so as to maintain a plasma concentrationof apomorphine of no more than about 5.5 nanograms per milliliter (5.5ng/ml). The sublingual administration usually takes place over a timeperiod in the range of about 2 to about 10 minutes, or longer. Theamount of apomorphine administered sublingually over this time periodpreferably is in the range of about 25 micrograms per kilogram (μg/kg)of body weight to about 60 μg/kg of body weight.

The apomorphine is administered preferably about 15 to about 20 minutesprior to sexual activity.

Apomorphine can be represented by the formula

and exists in a free base form or as an acid addition salt. For thepurposes of the present invention apomorphine hydrochloride ispreferred; however, other pharmacologically acceptable moieties thereofcan be utilized as well. The term “apomorphine” as used herein includesthe free base form of this compound as well as the pharmacologicallyacceptable acid addition salts thereof. In addition to the hydrochloridesalt, other acceptable acid addition salts are the hydrobromide, thehydroiodide, the bisulfate, the phosphate, the acid phosphate, thelactate, the citrate, the tartarate, the salicylate, the succinate, themaleate, the gluconate, and the like.

Illustrative preferred sublingual dosage forms are set forth in Table I,below.

TABLE I 150-Milligram Apomorphine Hydrochloride Sublingual Tablets 3-mgTablet Apomorphine Hydrochloride 2.00 wt-% Mannitol 66.67 wt-%  AscorbicAcid 3.33 wt-% Citric Acid 2.00 wt-% Avicel PH102 15.00 wt-%  MethocelE4M 10.00 wt-%  Aspartame 0.67 wt-% Magnesium Stearate 0.33 wt-% 4-mgTablet Apomorphine Hydrochloride 2.66 wt-% Mannitol 66.00 wt-%  AscorbicAcid 3.33 wt-% Citric Acid 2.00 wt-% Avicel PH102 15.00 wt-%  MethocelE4M 10.00 wt-%  Aspartame 0.67 wt-% Magnesium Stearate 0.33 wt-% 5-mgTablet Apomorphine Hydrochloride 3.33 wt-% Mannitol 65.34 wt-%  AscorbicAcid 3.33 wt-% Citric Acid 2.00 wt-% Avicel PH102 15.00 wt-%  MethocelE4M 10.00 wt-%  Aspartame 0.67 wt-% Magnesium Stearate 0.33 wt-%

If desired, and in order to facilitate absorption and thusbioavailability, the presently contemplated dosage forms can alsocontain, in addition to tabletting excipients, β-cyclodextrin or aβ-cyclodextrin derivative such as hydroxypropyl-β-cyclodextrin (HPBCD).Illustrative dosage forms containing HPBCD are shown in Tables II andIII, below.

TABLE II Apomorphine Hydrochloride Sublingual Tablets WithHydroxypropyl-β-Cyclodextrin mg/Tab Apomorphine Hydrochloride  4.0 HPBCD 5.0 Ascorbic Acid 10.0 PEG8000 39.5 Mannitol 39.5 Aspartame  2.0 TOTAL100.0 

TABLE III Apomorphine Hydrochloride Sublingual Tablets Withβ-Cyclodextrin mg/Tab Apomorphine Hydrochloride  5.0 β-Cyclodextrin 20.0Ascorbic Acid  5.0 Mannitol 68.9 Magnesium Stearate  1.0 D&C Yellow 10Aluminum Lake  0.1 TOTAL 100.0 

The onset of nausea can be obviated or delayed by delivering apomorphineat a controlled dissolution rate so as to provide circulating serumlevels and mid-brain tissue levels of apomorphine sufficient for anerection without inducing nausea. When apomorphine is administered at ornear the relatively higher amounts of the aforementioned dosage range,the likelihood of nausea onset can be reduced by concurrentadministration of a ganglionic agent (inhibitor of ganglionic response)such as nicotine or lobeline sulfate. For this purpose, the weight ratioof apomorphine to ganglionic agent is in the range of about 10 to about1.

Other antiemetic agents that can be used in conjunction with apomorphineare antidopaminergic agents such as metoclopramide, and thephenothiazines, e.g., chlorpromazine, prochlorperazine, pipamazine,thiethylperazine, oxypendyl hydrochloride, and the like. Also suitableare the serotonin (5-hydroxytryptamine or 5-HT) antagonists such asdomperidone, odansetron (commercially available as the hydrochloridesalt under the designation Zofran®), and the like, the histamineantagonists such as buclizine hydrochloride, cyclizine hydrochloride,dimenhydrinate (Dramamine), and the like, the parasympatheticdepressants such as scopolamine, and the like, as well as otheranti-emetics such as metopimazine, trimethobenzamide, benzquinaminehydrochloride, diphenidol hydrochloride, and the like.

Nicotine-containing dosage forms and domperidone-containing dosage formsare illustrated in Table IV, below.

TABLE IV Apomorphine Hydrochloride Sublingual Tablets Containing anAnti-Emetic Agent mg/Tab Apomorphine Hydrochloride  5.0 Ascorbic Acid 5.0 Mannitol 67.9 Magnesium Stearate  1.0 Nicotine  1.0 β-Cyclodextrin20.0 D&C Yellow 10 Aluminum Lake  0.1 TOTAL 100.0  ApomorphineHydrochloride  5.0 Ascorbic Acid  5.0 Mannitol 58.9 Magnesium Stearate 1.0 Domperidone 10.0 β-Cyclodextrin 20.0 D&C Yellow 10 Aluminum Lake 0.1 TOTAL 100.0 

The preferred sublingual dosage forms dissolve within a time period ofat least about 2 minutes but less than about 10 minutes. The dissolutiontime can be longer, however, if desired as long as the necessary plasmaconcentration of apomorphine can be maintained. More preferably, thedissolution time in water for the presently contemplated dosage forms isabout 3 minutes to about 5 minutes.

The present invention is illustrated further by the following studieswhich were focused on two specific objectives. The first was todetermine whether, relative to placebo response, patients who presentedwith “psychogenic” impotence (i.e., patients who were still capable ofachieving erections) demonstrated improved erectile function and/orenhanced sexual desire post-dosing with sublingual apomorphine (APO).The second objective was to determine what dose(s) of various forms ofsublingual APO are effective in this group of patients for inducing anerection that is sufficient for vaginal penetration.

Participating patients were selected from among those that initiallypresented with the complaint of impotence. These patients underwent athorough urological assessment by a urologist as well as an assessmentby a psychiatrist. Diagnostic testing for erectile difficulties wasextensive and included the following: biochemical profile, nocturnalpenile tumescence (NPT) monitoring, doppler flow studies,biothesiometry, corporal calibration testing with an intracorporalinjection of triple therapy and dynamic cavernosometry. These tests wereused to rule out any arterial, venous or peripheral neural causality ofimpotence. Any patients with abnormalities in any of these three areaswere excluded from entry to the trials. The inclusion/exclusion criteriafor all four pilot studies are set forth in Table V, below. Patients whomet all criteria were diagnosed as having impotence primarily of apsychogenic origin. If there were no known medical contraindications tothe use of a dopaminergic medication they were offered entry into an APOtrial.

Instructions were given regarding the protocol by the researchclinician, and an informed consent was obtained. Patients were advisedthat they were free to withdraw from the trial at any time withoutpenalty or prejudice. They were tested on at least three separate daysat three separate doses (placebo and two active medication doses) withan interval of no less than three days between. The experimental schemedescribed below was used in all four pilot studies.

Patients were seated in a comfortable chair and a RIGISCAN™ ambulatorytumescence monitor (Dacomed Corp., Minneapolis, Minn.) was placed on thepatient and the computer was set in the real time monitoring mode. Bloodpressure and heart rate were recorded pre-dosing with APO or placebo andat the end of the testing session. Visual analogue scales (VAS) werecompleted by the patient pre-dosing as well as post-dosing (at the endof the testing session). These scales reflected the patient's sense ofwell being, level of sedation, tranquilization, anxiousness, arousal andany changes in yawning behavior. In a single-blind fashion, apomorphineor placebo was administered to the patient sublingually. Doses of activemedication varied on the formulation of the apomorphine administered(liquid or tablet). Because of the possibility of nausea and thetolerance to this effect that prior dosing conveys, the patient wasgiven increasing doses at each testing. However, the patient was unawareof the dose that he was receiving (single-blind). Patients wereinstructed not to swallow the medication, but to keep it under theirtongue and allow it to be absorbed there.

Symptoms as they were volunteered were recorded by the researchclinician. If the patient complained of nausea or felt unwell in any wayhe was asked if he wanted to abort the trial. If the trial was aborted,the patient was given Gravol 50 mg p.o. at that time. The patient wasmonitored by the research clinician until these side-effects hadsubsided. He was asked to return the following week for retesting at thesame dose and was instructed to begin treatment with Domperidone 10 m.g.p.o. TID the day before and morning of his next session.

Patients not experiencing nausea or any other significant adverseeffects within fifteen minutes post-dosing with APO or placebo viewedsegments of standardized erotic videos to provide sexual stimulation.The following sequence of videos was viewed: a ten minute erotic video,a neutral video lasting between five and ten minutes in duration andfinally another ten minute erotic video. The duration of the testingsession for each dose level lasted between 45 and 60 minutes. Afterdetermining the most effective dose of apomorphine for the patient, hewas then offered APO for domestic trial at that dose.

Results of Pilot Studies 1 to 4

The frequency and the magnitude of erectile responses were documentedwith each dose of apomorphine or placebo. Data obtained from theRIGISCAN™ monitor was downloaded and each session was scanned. Erectionresponses were then scored for rigidity (%) and tumescence (cm.) at boththe tip and base of the penis and an overall score was given thatcorresponded to these parameters during the viewing of both erotic andneutral video segments (see Table VI, below). A score of less than 16indicated erectile dysfunction and a poor response to apomorphine atthat dose.

Visual analogue scales (See Table IX) were compared both pre- andpost-dosing, and examined for changes in feeling of well being, levelsof arousal, anxiousness, sedation/tranquilization and yawning behavior.Blood pressure and heart rate were also compared pre- and post-dosing.

Effects of apomorphine that were both reported to and observed by theresearch clinician were grouped into two categories: Adverse Effects(i.e., flushing, diaphoresis, nausea, vomiting, changes in bloodpressure or heart rate) or Primary Effects (i.e., yawning anderections).

Each pilot study was reviewed under the categories mentioned above.

Pilot Study #1

The initial formulation evaluated was liquid apomorphine administeredvia sublingual route. APO was prepared by a clinic pharmacist anddissolved in a solution of sodium metabisulfite and ethylenediaminetetraacetic acid (EDTA). The final concentration was 100 mg/ml. Patientswere tested on three separate occasions at three separate doses(placebo; 10 mg; 20 mg)

Twelve patients entered into this trial. All patients had reportederectile dysfunction greater than 1 year in duration. The age range inthis group was from 38 to 60 years. One patient withdrew after placeboand another withdrew after adverse effects at the 20 mg dose. That lefta total evaluable group of ten. All ten patients had previously receivedyohimbine HCl for erectile dysfunction. Eight had failed a trial ofyohimbine HCl. Of this group of eight, 6 were successful withapomorphine.

Seven (70%) were success (score of no less than 16 on both neutral anderotic video segments; Table VI) and three (30%) were categorized asfailures with apomorphine. Six out of the seven successful patientscontinued on with a domestic trial of apomorphine at the dose that gavethem the best response during testing. Three required treatment withDomperidone the day before and morning of apomorphine usage. The rangeof domestic use varied from two to seven months.

Analysis of visual analogue scales pre- and post-dosing with apomorphineindicated the following. At the end of the session patients were relaxedbut not sedated. There was no evidence of arousal or anxiousness.Yawning behavior changes were evident on these scales with the incidenceof yawning increasing between 15 and fifty minutes post-dosing and witheach increase in dosing. Each patient experienced between two to fiveyawns per session. These changes were not evident with placebo.

The primary effect of yawning was both reported by patients and observedat both 10 mg and 20 mg doses. No yawning was reported with placebo.Adverse effects were reported at both dose levels. Two patients who didnot experience nausea or diaphoresis were researched for similarities intheir patient profiles but none were found. Anywhere from ten to fifteenminutes post-dosing the other eight patients developed sudden onset ofvarious levels of nausea (and in one instance vomiting), diaphoresis,dizziness, double or blurred vision, decrease in both blood pressure andheart rate and pale or ashen coloring. Side effects varied from beingtransient and brief to lasting as long as from 30 to 40 minutes. Onepatient reported a stuffy nose starting approximately 30 minutespost-dosing and lasting for approximately 10 minutes. No adverse effectswere reported post placebo dosing.

The foregoing Pilot Study leads to the following conclusions:

1. Apomorphine is effective in inducing erectile episodes withoutincreasing libido in the “psychogenically” impotent male.

2. Both 10 mg and 20 mg doses produce erectile responses.

3. Both doses produced adverse effects (nausea, vomiting, diaphoresis,etc.) that would be unacceptable to patients and their partners,however. These effects can be counteracted with the use of Domperidone.

Pilot Study #2

The first sublingual tablet formulations evaluated were 2.5 and 5 mg.Patients were tested on three separate occasions at three separate doses(placebo; 2.5 mg, 5 mg).

A total of eight patients entered into this trial. All patients reportederectile difficulties for more that two years. The age range was from 38to 62 years. All had failed a trial of yohimbine HCl. One patientwithdrew from the trial after experiencing adverse effects at the 5 mgdose. That left a total of seven evaluable patients.

Two (29%) were successes (score of no less than 16; Table VI) and five(71%) were failures during lab testing. The two successful patients wentonto a domestic trial of apomorphine at the 2.5 mg dose which was themost effective and did not produce adverse effects. Both patients usedapomorphine at home for no less than two months with satisfactoryresults.

Analysis of visual analogue scales pre- and post-dosing with apomorphineindicated the same trends as with the liquid apomorphine preparation.Patients were relaxed but not sedated. No evidence of arousal oranxiousness was noted.

The primary effect of yawning was both reported by patients and observedat both 2.5 mg and 5 mg doses. The incidence of yawning increasedbetween fifteen and forty minutes post-dosing. At the 2.5 mg dose allpatients who failed testing had only one or two yawns per session. The 5mg dose not only produced adverse effects (nausea, diaphoresis,dizziness, blurred vision, facial flushing, drop in both heart rate andblood pressure) but also increased yawning responses to three to fivetimes per session. The two successful patients experienced three to fiveyawns at both the 2.5 mg and 5 mg doses. These changes were not evidentwith placebo.

At the end of Pilot Study #2 the following conclusions were made:

1. There appears to be a correlation between the effectiveness of thedose and yawning response (poor responders experience less yawning).

2. Both 2.5 and 5 mg doses produced erectile responses in some patients.The apparent 28% success rate was because of lab use only (failures werenot given drug to take home) and lack of available intermediate doses.

3. In some instances the 5 mg dose can produce adverse effects (i.e.,nausea, diaphoresis, etc.) that may be unacceptable to patients andtheir partners. These effects can be counteracted with theadministration of Domperidone or nicotine (e.g., by smoking).

4. The sublingual tablets were easy to administer and dissolved withinfive minutes.

Pilot Study #3

Apomorphine was evaluated as an aqueous intranasal spray (1.25 mg perpuff). The first patient was an anxious, 53 year old male who had beenexperiencing erectile dysfunction for two years. This patient hadpreviously failed a trial of yohimbine.

He was tested on three separate occasions at three separate doses(placebo, 2.5 mg; 3.75 mg) and was categorized as a failure with thescore of less than sixteen on both erotic and neutral video segments. Heexperienced yawning with both 2.5 mg and the 3.75 mg and was successfulwith this trial for two months until he inadvertently increased thedose. Adverse effects occurred within five minutes post-dosing (nauseaand vomiting, dizziness, double and blurred vision, diaphoresis, andashen coloring). The patient refused to retry medication after thisincident. He stated he did not like this formulation.

Patient No. 2 was twenty-one year old male with erectile problems of aduration of three years. He had failed a previous course of yohimbineHCl. Ten minutes post-dosing with apomorphine at 2.5 mg he experiencedyawing for a total of five yawns, and then experienced immediately majorhemodynamic adverse effects. These included pale and ashen coloring,diaphoresis, nausea and vomiting, blurred vision, hypotension with ablood pressure of 70/50. Twenty minutes post adverse effect, vital signswere stable. The patient was feeling well, and coloring was good. Thispatient was then dropped from further testing.

Although the intranasal administration was effective in eliciting anerection, further testing of this intranasal formulation of apomorphinewas discontinued because of possible overdose and increased sideeffects. The foregoing experience illustrates the need for reliable andrelatively safer dosage forms, however.

Pilot Study #4

New sublingual tablet formulations of apomorphine at 3, 4 and 5 mg doses(Table I, above) were evaluated. Patients were tested on at least threeseparate occasions on at least three separate doses (placebo; 3 mg; and4 mg). A 5 mg sublingual dose was also tested in some patients. Theresults of this study are summarized in Tables VII and VIII A-C, below.

To date, twelve patients have been completely evaluated on thisformulation. All patients reported erectile dysfunction for more thantwo years. The patients' age range was thirty-nine to sixty-six years.Three patients had been successful with yohimbine HCl in the past, andtwo had previously not tried this compound. Seven patients of this groupof twelve had previously failed a trial of yohimbine HCl. Of this lattergroup of seven, four were successfully treated with apomorphine.

Eight (67%) have been successful with apomorphine to date. Four (33%)were failures with apomorphine. Both 3 mg and 4 mg doses producederectile responses. Several patients went on to a trial of the 5 mgsublingual dose which did not appear to be more effective than therelatively lesser doses in terms of erectile response. All eight of thesuccessful patients continued on with the domestic use for a time periodof one to four months. All patients reported good erectile activity andno side effects.

Analysis of visual analogue scales, both pre- and post-dosing withapomorphine, again indicated that the patients were relaxed but notsedated, and did not have feelings of arousal or anxiousnesspost-dosing. The new formulations tested (3 mg; 4 mg; and 5 mg) weredevoid of adverse effects. The patients felt well post testing, and didnot report or demonstrate any adverse effects that had traditionallybeen seen with the administration of previous apomorphine liquid andintranasal preparations (Pilot Studies No. 1 and No. 3). The primaryeffect of yawning was still reported and observed at all doses, but thenumber and frequency of yawns was small (one or two).

The foregoing pilot study shows that 3-mg, 4-mg and 5-mg apomorphinedoses are effective in inducing penile erections, and also that thereare no serious adverse effects with these preparations. Domestic use ofthese preparations was well accepted by patients and their partners.They were content with the convenience of dosing approximately fifteenminutes prior to sexual activity. All patients have stated that this wasmore acceptable than dealing with dosing on a routine basis.

TABLE V Inclusion/Exclusion Criteria INCLUSION CRITERIA:  1. Age 18-66years.  2. NPT circumference increase of 1.5 cm or more on one nightand >70% rigidity.  3. ICI circumference increase of 1.5 cm or moreand >70% rigidity. EXCLUSION CRITERIA:  1. Currently severe or lifethreatening systemic disease.  2. Clinically significant ECGabnormalities.  3. Personal or first degree family history of epilepsy. 4. Abnormal: Hepatic/renal function Hematology  5. Low: pre-trialtestosterone Low or High: LH High: Prolactin  6. Hypertension requiringtreatment.  7. History of depression requiring treatment withantidepressants, ECT, or hospitalization.  8. Symptomatic ischemic heartdisease/or MI within the last three months.  9. Diabetes. 10. Failure toobtain informed consent. 11. Legal cases. 12. Unable or unwilling tocomply with protocol. 13. Drinks more than (on average) 45 units alcoholper week/or uses illicit drugs. 14. History of syncope. 15. ProhibitedDrugs: sympathetic or parasympathetic types drugs, Beta blockers,Vasodilators, psychotropic medications, tranquilizers, thiazides,Captopril, Verapmil, Furosemide, Spironolactone, Metochlopramide,Cimetidine or other drugs which are likely to influence erectilefunction.

TABLE VI Response to Erotic Videotape 1. Maximum increase in penilecircumference Circumference (cms.) Score 0-<0.5 cm. 0 0.5-<1.0 cm. 11.0-<1.5 cm. 2 1.5-<2.0 cm. 3 2.0-<2.5 cm. lasts <1 min. 4 2.5 or morelasts <1 min. 5 2.0-<2.5 cm. lasts at least 1 min. 6 2.5 or more lastsat least 1 min. 7 3.0 or more lasts at least 5 min. 8 3.0 or more lastsat least 10 min. 9 Score  A. Maximum increase in penile tipcircumference _(———) B. Maximum increase in penile basal circumference_(———) 2. Maximum penile rigidity Rigidity (%) Score 0-<10 0 10-<20 120-<30 2 30-<40 3 40-<50 4 50-<60 5 60-<70 6 70-<80 7 80-<90 8 90-100 9Score  C. Maximum penile tip rigidity _(———) D. Maximum penile basalrigidity _(———) 3. Total score (A, B, C & D) _(———) _(———) A score ofless than 16 indicates erectile dysfunction

TABLE VII Summary of Results from Pilot Study #4 in Psychogenic PatientsApomorphine · HCl Sublingual Tablet PLACEBO 3 Mg Dose (μg/kg) 4 Mg Dose(μg/kg) 5 Mg Dose (μg/kg) Patient # (Wt., kg) Erotic #1 Neutral #1Erotic #2 Neutral #2 Erotic #3 Neutral #3 Erotic #4 Neutral #4 401(68.5) 31 28  29  (44) 27  (44) 33  (58) 27  (58) 402 (70.3) 12 4 12 (43) 4  (43) 17  (57) 6  (57) 403 (118) 16 4 22* (25) 5  (25) 22* (34)25  (34) 404 (83.5) 24 10  26* (36) 17  (36) 25* (48) 17  (48) 405 (78)11 1 18* (38) 6  (38) 12  (51) 8  (51) 10 (64) 5 (64) 406 (80) 14 5 18*(38) 17  (38) 17* (50) 2  (50) 407 (100)  8 0 18* (30) 4  (30) 10  (40)3  (40) 408 (86.2) 28 18  32  (35) 21  (35) 34  (46) 22  (46) 409 (93) 2 0 4  (32) 1  (32) 8  (43) 6  (43)  5 (54) 4 (54) 410 (80)  3 0 13 (38) 16  (38) 8  (50) 7  (50) 411 (98) 13 5 26* (31) 23* (31) 24* (42)20  (42) 412 (73)  7 3 7  (41) 1  (41) 28* (55) 19* (55) *Patients withscore higher than 16 (see scoring table) are positive respondents. Outof 12 patients who were treated in this study, 5 showed improvement atboth 3 mg and 4 mg doses. Two (2) showed response only at one dose. Noimprovement in clinical response was observed at 5 mg dose.

The data of Pilot Study #4 were analyzed in two ways. First, meanerectile function was compared across placebo, 3 mg and 4 mg doses undertwo stimulus backgrounds, erotic and neutral. Next erectile functionscores were dichotomized, with values less than sixteen considered toreflect erectile insufficiency.

A. Mean Erectile Function

Table VIII A shows means and standard errors for all three treatmentsunder both backgrounds, erotic and neutral. Means were compared using arestricted maximum likelihood generalized linear model containing twomain effects, treatment and stimulus, and the treatment by stimulusinteraction. An appropriate variance-covariance structure wasestablished for the underlying statistical model using Akaike'scriterion. Table VIII B presents the statistical results for the maineffects of treatment and of stimulus, for the treatment by stimulusinteraction, and for orthogonal contrasts within the erotic and neutralconditions. It can be seen that the treatment main effect (i.e., generaldifference across treatment conditions without regard to stimulusbackground) is statistically significant; that the main effect ofstimulus (i.e., general difference across stimulus backgrounds withoutregard to treatment) is statistically significant; and that thetreatment by stimulus interaction is not statistically significant.These findings imply that active treatment is more effective thanplacebo and that this finding, although stronger when using an eroticstimulus, is true regardless of stimulus background (see FIG. 1). Theorthogonal (statistically independent) contrasts confirm that activetreatment is superior at a statistically significant level under botherotic and neutral conditions, but also indicate that the differencebetween the 3 mg and 4 mg dose does not exceed that expected by chancefor the number of patients (12) used in this study.

B. Percent Successful Erectile Function

FIG. 2 and Table VIII C show that the statistically significantsuperiority of active over placebo treatment, regardless of stimulusbackground, is maintained when the erectile function scores areclassified to reflect success (score at least 16) or failure (score lessthan 16).

TABLE VIII A Mean and Percent Successful Erectile Function StimulusTreatment N Mean (SE) Percent (SE) Erotic Placebo 12 14.08 (2.69) 33.33(13.61) 3 mg 12 18.75 (2.51) 66.67 (13.61) 4 mg 12 19.83 (2.67) 66.67(13.61) Neutral Placebo 12  6.50 (2.45) 16.67 (10.76) 3 mg 12 11.83(2.68) 50.00 (14.43) 4 mg 12 13.50 (2.61) 50.00 (14.43) Note: Mean (SE)from SAS PROC UNIVARIATE. Percent (SE) from SAS PROC CATMOD.

TABLE VIII B Anova for Mean Erectile Function EFFECT DF F P-valueTreatment 2.66 11.56 0.0000 Stimulus 1.66 37.14 0.0000 Treatment byStimulus 2.66  0.10 0.9046 Contrasts Erotic: Placebo vs. Treatment 1.66 9.30 0.0033 Erotic: 3 mg vs. 4 mg 1.66  0.30 0.5849 Neutral: Placebovs. Treatment 1.66 13.03 0.0006 Neutral: 3 mg vs. 4 mg 1.66  0.71 0.4014Note: Restricted maximum likelihood analysis performed using SAS PROCMIXED.

TABLE VIII C Logistic Regression for Percent Successful ErectileFunction EFFECT DF X² P-value Treatment 2 15.36  0.0005 Stimulus 1 5.140.0233 Treatment by Stimulus 2 0.00 1.0000 Contrasts Erotic: Placebo vs.Treatment 1 9.60 0.0019 Erotic: 3 mg vs. 4 mg 1 0.00 1.0000 Neutral:Placebo vs. Treatment 1 9.60 0.0019 Neutral: 3 mg vs. 4 mg 1 0.00 1.0000Note: Analysis performed using SAS PROC CATMOD.

TABLE IX Visual Analogue Scale (VAS) (to be completed by the patient)Please mark each line clearly at the point which indicates how you arefeeling right now. Each line represents the full range of each feeling.(There are no right or wrong answers) Score (mm)  1. Alert _(—————————)Drowsy _(————)  2. Calm _(—————————) Excited _(————)  3. Yawning_(—————————) Not Yawning _(————)  4. Fuzzy _(—————————) Clear Headed_(————)  5. Well Coordinated _(—————————) Clumsy _(————)  6. Tired_(—————————) Energetic _(————)  7. Contented _(—————————) Disconnected_(————)  8. Troubled _(—————————) Tranquil _(————)  9. Mentally slow_(—————————) Quick Witted _(————) 10. Tense _(—————————) Relaxed _(————)11. Attentive _(—————————) Dreamy _(————) 12. Stomach Upset _(—————————)Feeling Well _(————) 13. Anxious _(—————————) Carefree _(————) (measurefrom left to right)

Dose Evaluation Study

Clinical response to sublingual administration of apomorphine wasevaluated utilizing a group of 60 non-vasculogenic impotent patients.Each patient had a history of erectile dysfunction for at least 3months, normal biothesiometry response, and normal cavernosometryresults.

The patients were divided into seven groups. Each group received apredetermined dosage of apomorphine for 20 days in the form ofapomorphine hydrochloride tablets 20 minutes prior to intercourse. Sevendifferent dosages were evaluated—3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg and10 mg The tablet constituents were those shown in Table I, above.Assessment of response was made on the basis of the patient's report ofhis experience. A response was deemed positive when the patientexperienced an erection sufficiently rigid to effect penetration. Sideeffects such as nausea and/or vomiting, if present, were noted as well.

The results of this study are compiled in Table X, below.

TABLE X Results of Dose Evaluation Study Positive No. of Dosage,Responses Nausea Vomiting Patients mg No. % No. % No. %  5 3 0  0 0  0 0 0  5 4 2 40 1 20 1 20 10 5 5 50 2 20 1 10 10 6 7 70 2 20 2 20 10 7 7 702 20 2 20 10 8 7 70 3 30 3 30 10 10  8 80 4 40 4 40

From the foregoing Table it can be seen that at a 4-mg dosage 40 percentof patients had a positive response, at a 5-mg dosage 50 percent ofpatients had a positive response, at 6-mg, 7-mg, and 8-mg dosages 70percent of patients had a positive response and at a 10-mg dosage 80percent of patients had a positive response. However, the incidence ofside effects increased as well as the dosage was increased.

The aforesaid apomorphine dosage forms are also well suited fordiagnosing male human patients suffering from male erectile dysfunction.For diagnostic purposes, at least about 3 milligrams of apomorphine areadministered sublingually to the patient and the patient is exposed to avisual erotic stimulus, e.g., an erotic videotape, while the patient'sresponse thereto is monitored. If deemed desirable for diagnosticpurposes, up to about 10 milligrams of apomorphine can be administeredto the patient.

In particular, the patient's maximum increase in penile circumference(preferably tip as well as basal) is determined and the patient'smaximum penile rigidity (preferably tip as well as basal) is determined.The determined circumferential increase and rigidity values are thencompared against a predetermined base value. Equivalent methods ofdetermining tumescence and rigidity can also be utilized.

Pilot Study #5

A clinical study, “Absorption and pharmacokinetic evaluation ofapomorphine after sublingual and intravenous routes of administration”compared the absorption and pharmacokinetic profile of apomorphineadministered intravenously and slowly at a 1 mg dose with apomorphinesublingual tablets at doses of 4 mg (Table I) and 8 mg administered on 3occasions, 4 days apart, over a 12 day period in a cross-over studydesign. The tolerance for apomorphine for each route and each doseadministered was determined.

The study was conducted as an open-label, single center, 3-way crossoverdesign. The study population was seven healthy, Caucasian malevolunteers between 18 and 35 years of age. A 15-day pre-study evaluationperiod was followed by a 12-day active treatment phase. Three doses (oneintravenous; 2 sublingual) were administered to each subject in randomorder 4 days apart. A total of 36 serum samples were obtained from eachsubject at the following time periods: 0, 2, 3, 5, 10, 20, 30 and 45minutes; and 1, 2, 3, 4 and 6 hours post dose administration.

Safety was assessed within 15 days prior to study start and within oneweek after the last dose was administered. General physical examinationwas performed. Change from baseline in vital signs, height/weightmeasurements, ECG, orthostatic arterial pressures, heart rate, serumchemistry profile, hematology profile and urinalysis were recorded.Adverse experiences were recorded at each visit and tabulated.

Data Analysis

1. Pharmacokinetic Analysis

Pharmacokinetic analysis was performed by compartmental andnoncompartmental methods described below. Nonlinear, iterative,least-squares regression analysis was performed with the computerprogram, PPHARM (Simed Co., Philadelphia, Pa.).

A. Compartmental Analysis

The apomorphine plasma concentration data for each subject followingintravenous administration was fitted to two-compartment open model witha first order input function as described by the following equations.

Plasma apomorphine concentration was described for intravenousadministration data by equation (1):

C _(t) =Ae ^(−αt) +Be ^(−βt)   (1)

Plasma apomorphine concentration was described for sublingual tabletadministration by equations (2) and (3): $\begin{matrix}{C_{t} = {\frac{F\quad D\quad k_{a}}{V_{d}\left( {k_{a} - k_{e}} \right)}\left( {^{- {k_{e}{({t - t_{lag}})}}} - ^{- {k_{a}{({t - t_{lag}})}}}} \right)}} & (2)\end{matrix}$

C _(t) =Ae ^(−α(t−t) ^(_(lag)) ⁾ +Be ^(−β(t−t) ^(_(lag)) ⁾ +Ce ^(−k)^(_(a)) ^((t−t) ^(_(lag)) ⁾   (3)

In the above equations, C_(t) is the apomorphine plasma concentration attime t; F is the relative bioavailability, which is assumed to be onefor intravenous administration; K_(a) is the first order rate constantfor sublingual absorption; K_(e) is the first order rate constant forelimination; V_(d) is the volume of distribution; D is the apomorphinedose; t is time; t_(lag) is the lag time before onset of sublingualabsorption; A, B, C are the intercepts of the distribution, elimination,and absorption phases, respectively; α is the distribution rateconstant; β is the elimination rate constant; and K_(a) is theabsorption rate constant.

Initial estimates of the intravenous and sublingual pharmacokineticparameters were obtained with the computer program PPHARM (Simed Co.,Philadelphia, Pa.). These initial estimates were used to fit the data toequations (1), (2) and (3) by nonlinear iterative least squaresregression analysis. The results are shown graphically in FIG. 4. Theestimate of F (relative bioavailability) for sublingual administrationwas obtained from the noncompartmental analysis outlined below.

Visual inspection of the fitted curves, analysis of the residual plots,the Akaike information criterion, and correlation coefficients betweenobserved and calculated values were used to select the appropriatepharmacokinetic model for each set of plasma concentration versus timedata. A weighting factor was used to fit the data.

The regression analysis provided the final estimates of thepharmacokinetic parameters: V_(d), K_(e), K_(a), and t_(lag) fromequation (2), and A, B, C, α, β, k_(a), and t_(lag) from equation (3).The maximum plasma concentration (C_(max)), time to maximum plasmaconcentration (T_(max)), and V_(d) (volume of distribution) werecalculated using standard compartmental pharmacokinetic equations(Gibaldi, M. & Perrier, D. Pharmacokinetics, 2d edition, Marcel Dekker,Inc. New York, 1982).

The values for C_(max) and T_(max) obtained by visual inspection of theplasma concentration versus time curve were reported for comparativepurposes. Model dependent and independent pharmacokinetic parameters(presented in Tables XI-XIV) were calculated for each patient using thebest fit of Equation (3) to the data.

B. Noncompartmental Analysis:

The area under the curve, AUC_(0−inf), was determined by adding theAUC_(0−last) to the AUC_(t−last), where AUC_(t−last)=C_(t)/R_(e), C_(t)is the plasma concentration at time ^(t), and R_(e) is K_(e), the firstorder rate constant for elimination.

If the plasma concentration versus time data for a subject could not beadequately fit to equation (1), (2) or (3), the K_(e) was determined bylinear regression analysis of the log plasma concentration versus timeduring the post-absorption phase. Estimates of noncompartmentalparameters C_(max) and T_(max) were obtained from visual inspection ofthe plasma concentration time curves.

The relative bioavailability (F) for a sublingual dose was calculated bythe following equation: $\begin{matrix}{F = \frac{{AUC}_{SL}*D_{IV}}{{AUC}_{IV}*D_{SL}}} & (4)\end{matrix}$

2. Statistical Analysis:

An analysis of variance (ANOVA) for a three-way crossover study designwas utilized to compare the pharmacokinetic parameters (AUC, C_(max),and t_(lag)) determined as described above for the intravenousadministration at 1 mg dose and those determined for the sublingualadministration of apomorphine at the 4 mg and the 8 mg doses. The ANOVAwas tested for the presence of any period or residual carryover effectsin the data. Statistical significance was set at an alpha level equal to0.05. The ability of the ANOVA to detect both a 20% difference and theobserved difference between the sublingual and intravenouspharmacokinetic parameters was determined. In addition to the ANOVA, the95% confidence interval of the percent difference between the sublingualand SC parameters was calculated from the error variance and degrees offreedom of the ANOVA model.

The data were summarized as the mean ± standard deviation in TablesXI-XIV below.

TABLE XI NONCOMPARTMENTAL PHARMACOLOGIC PARAMETERS (MEAN ± SD) AND RANGEIV Administration 4 mg Dose 8 mg Dose Parameter Mean ±SD Low High Mean±SD Low High Mean ±SD Low High Ke (min⁻¹) 0.0237 0.0140 0.0091 0.04320.0156 0.0138 0.0038 0.0336 0.0056 0.0036 0.00222 0.0102 T_(½)(min)39.44 0.219 16.04 76.49 89.18 75.43 20.62 183.60 176.30 112.30 68.09314.6 Tmax (min) 2.286 1.254 1.000 5.000 17.50 18.48 5.000 45.00 52.5085.10 5.000 15.00 Cmax (min) 8.364 3.886 3.400 12.90 0.8375 0.68480.3000 0.8500 2.069 2.366 0.5750 1.150 AUC (0-Inf) 206.9 45.47 140.8260.1 31.64 18.62 10.13 55.55 339.9 459.2 15.00 316.6 (min*ng/ml) Cl(ml/min) 0.0051 0.0012 0.0038 0.0071 0.0456 0.0361 0.0180 0.0988 0.20560.2460 0.0253 0.5333 Vd (beta) (ml) 0.2344 0.1532 0.0056 0.4982 4.0762.053 1.017 5.277 69.09 115.80 7.932 64.27 Vd (SS) (ml) 0.1942 0.08170.1357 0.3401 1.836 0.7112 0.999 2.475 46.30 74.46 6.523 12.42 MRT (min)40.29 18.90 20.14 75.32 64.25 55.14 15.12 137.5 143.7 148.0 23.29 329.3F* (% Relative — — 0.04 (4.0%) 0.21 (21%) Bioavailability) F* =(AUC_(SL)*DOSE_(IV))/(AUC_(IV)*DOSE_(SL)) Cl = clearance Vd = volume ofdistribution @ β stage. Vd (SS) = volume of distribution steady stateMRT = means residual time

TABLE XII Noncompartmental Pharmacokinetic Parameters (Mean ± SD) for IVAdministration (1 mg) n = 7 Subject Subject Range #1 #2 #3 #4 #5 #6 #7Mean ±SD Low High Ke (/min) 0.0432 0.0129 0.0091 0.0419 0.0168 0.01500.0268 0.0237 0.0140 0.0091 0.0432 T_(½)(min) 16.04 53.79 76.49 16.5641.22 46.18 25.84 39.44 21.92 16.04 76.49 Tmax (min) 2.000 2.000 2.0002.000 2.000 5.000 1.000 2.286 1.254 1.000 5.000 Cmax (min) 8.400 11.2004.150 12.250 12.900 3.400 6.250 8.364 3.886 3.400 12.900 AUC (0-Inf)140.8 255.4 221.5 177.1 224.6 169.0 260.1 206.9 45.47 140.8 260.1(min*ng/ml) Cl (ml/min) 0.0071 0.0039 0.0045 0.0056 0.0045 0.0059 0.00380.0051 0.0012 0.0038 0.0071 Vd (beta) (ml) 0.1643 0.3039 0.4982 0.00560.2648 0.2574 0.1466 0.2344 0.1532 0.0056 0.4982 Vd (SS) (ml) 0.14300.1512 0.3401 0.1147 0.2174 0.2574 0.1357 0.1942 0.0817 0.1357 0.3401MRT (min) 20.14 38.62 75.32 20.32 48.82 43.50 35.31 40.29 18.90 20.1475.32

TABLE XIII Noncompartmental Pharmacokinetic Parameters (Mean ± SD) forSublingual Administration (4 mg Dose) n = 4 Subjects Range #1 #3 #6 #7Mean ±SD Low High Ke (/min) 0.0188 0.0336 0.0060 0.0038 0.0156 0.01380.0038 0.0336 T_(½)(min) 36.78 20.62 115.7 183.6 89.18 75.43 20.62 183.6Tmax (min) 10.00 10.00 5.000 45.00 17.50 18.48 5.000 45.00 Cmax (ng/ml)0.8500 1.8000 0.3000 0.4000 0.8375 0.6848 0.3000 0.8500 AUC (0-Inf)10.13 29.25 31.64 55.55 31.64 18.62 10.13 55.55 (min*ng/ml) Cl (ml/min)0.0988 0.0342 0.0316 0.0180 0.0456 0.0361 0.0180 0.0988 Vd (beta) (ml)5.241 1.017 5.277 4.769 4.076 2.053 1.017 5.277 Vd (SS) (ml) 1.494 0.9992.377 2.475 1.836 0.7112 0.999 2.475 MRT (min) 15.12 29.23 75.19 137.4764.25 55.14 15.12 137.47

TABLE XIV Noncompartmental Pharmacokinetic Parameters (Mean ± SD) forSublingual Administration (8 mg Dose) n = 4 Subjects Range #2 #3 #4 #6Mean ±SD Low High Ke (/min) 0.0067 0.0032 0.0120 0.0022 0.0056 0.00360.0022 0.0102 T_(½)(min) 104.0 218.4 68.09 314.6 176.3 112.3 68.09 314.6Tmax (min) 180.0 10.00 15.00 5.000 52.50 85.10 5.000 180.0 Cmax (ng/ml)5.600 1.150 0.9500 0.5750 2.069 2.366 0.5750 5.600 AUC (0-Inf) 996.6316.6 31.25 15.00 339.9 459.2 15.00 996.6 (min*ng/ml) Cl (ml/min) 0.0080.0253 0.2560 0.5333 0.2056 0.2460 0.008 0.5333 Vd (beta) (ml) 1.2047.932 25.15 242.1 69.09 115.8 1.204 242.1 Vd (SS) (ml) 157.9 8.320 6.52312.42 46.30 74.46 6.523 157.9 MRT (min) 196.7 329.3 25.48 23.29 143.7148.0 23.29 329.3

TABLE XV Summary of Pharmacokinetic Parameters for Apomorphine HCl inHumans PUBLISHED DATA Montastruc, Durif, F. et al., J.L., et al.  Clin.Clin. Neuro- Neuropharm. Gancher, S.T., et al.  pharmacol. 16:157-166Movement Disorders 14:432-437 THIS STUDY (1933) 6:212-216 (1991).(1991). ROUTE i.v. s.l. s.l. s.l. s.l. s.l. s.c. i.v. s.l. s.c. #Subjects 7 7 7 7 7 5 5 5 9 9 # Tablets × n/d 1 × 4 1 × 8 7 × 3 14 × 3 3× 6 n/a n/a 10 × 3 n/a Strength (mg) Dose (mg/kg) 0.01 0.06 0.114 0.30.6 0.25 0.02 0.038 0.42 0.04 C_(max) (ng/ml) 8.3 0.83 2.07 7.5 22.714.3 19.36 31.2 28 26 T_(max) (min) 2.2 17.5 52.5 31.5 38.3 45 6.5 6.741 18 AUC 207 31.6 340 929 2,277 1,057 592.7 881.1 1,882 837 (min*ng/ml)Cl (l/hr/kg) 4.37 n/d n/d 2.1 1.8 n/d n/d n/d n/d n/d Vd (l/kg) 3.352.33 2.07 3.4 2.8 n/d n/d 0.043* n/d n/d MRT (min) 40.3 64.2 143.7 128125 n/d n/d n/d n/d n/d T_({fraction (1/2 )}) (min) 39.4 89.2 176.3 7270 n/d n/d n/d n/d n/d Bioavailability (F) n/a 4% 21% 10% 10% 17% n/an/a n/d n/a n/d = not done n/a = not applicable *Calculated Clin.Neuropharm. 16:157-166 (1993)

The results, summarized in Tables XI-XIV above and shown graphically inFIG. 4, show that the plasma concentration of apomorphine drops quicklywhen the drug is administered intravenously. In contrast, the plasmaconcentration of apomorphine rises slowly to a lower level whenadministered sublingually.

The importance of these findings is put into perspective when comparedto information on the administration of apomorphine that is available inthe literature (Table XV). The sublingual administration of apomorphineby the present invention produced a lower plasma concentration than theadministration and dosage regimes listed for previous reports.

Pilot Study #6

A clinical study of patient tolerance of escalating doses in sublingualtablet administration of APO for the treatment of psychogenic maleerectile dysfunction was performed. The pilot study compared the effectsof sublingual tablet administration of placebo, and 4, 6 and 8 mgapomorphine hydrochloride (APO) on male erectile dysfunction as measuredby Rigiscan™ monitoring and self-reported satisfaction with thetreatment results.

The study included 50 men with psychogenic male erectile dysfunction(MED). The study was conducted in three phases. In the first phase, thesubject's penile erectile response (measured with the Rigiscan™ambulatory tumescence monitor) was evaluated. The subject received aplacebo tablet for sublingual administration and then viewed a 30-minutevideo consisting of two 10-minute erotic sequences separated by a10-minute neutral sequence. Subjects completed a visual analogue scalequestionnaire (VAS, Table VI) about their feelings and well-being.

In the second phase, subjects returned to the clinic for four visits,each visit one week apart. Subjects received one sublingualadministration of either placebo, or 4, 6 and 8 mg APO at each visit.Doses of APO were administered in ascending order with the placebo beingrandomly assigned for use at one of the four visits. The proceduresperformed before and after drug administration were the same as those inthe first phase. After completion of the fourth visit, the investigatordetermined for each subject the most effective and well-tolerated APOdose for home use in the third phase of the study.

The third phase, a home-use phase, lasted 5 weeks. During this phase,subjects attempted coitus at least once each week after taking a singleAPO tablet. After each attempt the subject and his partner completed aSexual Function questionnaire (Table XVI). Subjects had a finalevaluation at the end of the 5-week, home-use phase.

Fifty males with psychogenic MED were enrolled in this three phasetrial. The first aim of this study was to determine the safety andtolerance of APO in the treatment of MED. Several adverse eventsdirectly linked with administration of APO in humans were expected:yawning, nausea, vomiting, and cardiovascular effects. Indeed, nauseawas the primary adverse event reported in this trial with an overallincidence of less than 13% of the subjects for all administered dosesand only two cases were considered severe. The incidence of vomiting wasless than 3% for all administered doses.

Hypotension was reported as an adverse event in some subjects in thisstudy, along with bradycardia, dizziness, syncope, and pallor. Onlysingle cases of hypotension and pallor were judged severe in this study.Increased sweating and fatigue were also reported. One of the cases ofincreased sweating was considered severe. The other severe adverseevents (mouth edema, dysphagia, upper respiratory tract infection) werejudged unrelated to treatment.

Changes in the serum chemistry values and vital signs paralleled theadverse event reports. There were no clinically significant changesexcept for one subject judged to have abnormal liver function of unknownorigin. There were no clinically significant changes in the blood orurinalysis values due to drug.

The efficacy of APO was evaluated during the first two phases of thestudy in which subjects were attached to the Rigiscan™ monitor. Subjectswere initially treated with placebo in the first phase. In the secondphase, patients received 4, 6 and 8 mg APO tablets with a placebo tabletrandomly interspersed in the treatment.

There were highly significant effects of APO treatment compared toplacebo. These observations indicate that APO has effects on penilefunction in both erotic and neutral environments (Tables XVII-XIX). Allsummed scores showed significant treatment effects at one or more of thethree doses of APO. The overall Rigiscan™ score results were significantto highly significant for a treatment effect of 4, 6 and 8 mg comparedto the initial placebo. In addition, most of the treatment effects weresignificant to highly significant compared to the second placebo.

The effects in the erotic video sequences were larger than the effectsin the neutral video sequence (TABLES XVII-XIX). Effects in erotic videosequence one were larger than the effects in erotic video sequence two(TABLE XVII). More significant treatment effects were seen in responseto the neutral video sequence, but this reflects the larger number ofsubjects in this data subset, as one center did not show the eroticvideo sequences. All doses of APO were effective in causing erections(Rigiscan™ reading ≧15 in the presence of erotic stimulation; TABLEXVII).

During the third phase, subjects had recorded at baseline, theirsatisfaction, erection, number of attempts, and successful intercourseon a VAS scale. Evaluable subjects first recorded a success rate, thencompleted VAS for erection results and satisfaction with intercoursefollowing take-home treatment. Success rate was calculated for mg aswell as μg/kg body weight doses (males). Several evaluations of the datawere made including the male and female responses to treatments. Theoverall average success rate is 69% with APO treatment which is muchhigher than the average baseline rate 28% (Tables XX, XX1).

The success rate showed numerical increase at tablet strength from 4 mgto 6 mg, but a decrease at 8 mg (TABLE XX). The highest success rate was73% in both males and females at a tablet strength of 6 mg (TABLE XX).When the dosage is examined as a function of body weight, a dosage rangeof 50-74 μg/kg gave the highest success rate(: 82%) in females and (80%)in males (Table XXI). The dosage range of 35-50 μg/kg gave the highestsuccess rate.

The optimal response was observed with 4 or 6 mg APO sublingual tabletswhich caused erections in the majority (72%) of men with male erectiledysfunction (MED) with few severe adverse effects.

TABLE XVI SEXUAL FUNCTION STUDY HOME QUESTIONNAIRE - Male Please answerquestions within 12-24 hours of taking sublingual tablet.Initials:_(————) Subject #:_(————) Today's Date:_(———————) Time:_(————)Date Table Taken:_(————) Time:_(————) The lines below represent the fullrange of feeling or response. Please mark each line clearly with avertical (straight up and down) stroke at the point which representsyour response. (There are no right or wrong answers. Do not write inboxes on right.) 1. What was your erection result after taking thesublingual tablet? Rigid Erection No Suitable for Erection_(————————————————————————————) Penetration [ ] 2. Did you haveintercourse with wife/partner after taking tablet? [ ] Yes [ ] No IF NO,please circle all 0 - No erection. reasons that apply: 1 - Erection notsufficient for penetration. 2 - Felt sick after after taking tablet.(Describe below in #4.) 3 - I decided not to participate in intercourse.4 - Wife/partner decided not to participate. 5 - Unrelated interruption(example, telephone call). 6 - Wife/partner menstruating. 7 - Other,explain: _(——————————————————) _(——————————————————————————) 3. What wasyour level of satisfaction with this attempt at sexual intercourse?Extremely Extremely Unsatisfied _(————————————————————————————)Satisfied [ ] 4. Please describe any adverse reactions you experiencedafter taking the sublingual tablet. (Indicate when the reaction startedand stopped, and any intervention taken i.e. “nosebleed on 5/1/94, useda cold compress”.) _(—————————————————————————————————————)_(—————————————————————————————————————)_(—————————————————————————————————————) 5. Other comments?————————————————————————————— _(—————————————————————————————————————)

TABLE XVII Total Rigiscan Scores by Phase Mean ± SEM Phase II VideoPlacebo 1 Placebo 2 4 mg 6 mg 8 mg Phase I Phase II Erotic 1 11.44 ±1.77 13.38 ± 2.05 15.31 ± 1.76* 17.09 ± 1.64** 19.84 ± 1.61** N = 31-36Erotic 2 11.39 ± 1.70 13.31 ± 1.88 15.26 ± 1.72* 16.44 ± 1.98*  17.79 ±1.96** N = 29-36 Neutral  7.98 ± 1.24  7.49 ± 1.26  11.11 ± 1.30** 12.76± 1.12** 11.98 ± 1.37** N = 41-48 Corresponding p-values (placebl1/placebo 2) Erotic 1 — 0.3274 0.0120 0.0007 0.0001 — — 0.1405 0.01660.0005 Erotic 2 — 0.4013 0.0276 0.0196 0.0007 — — 0.1907 0.1365 0.0091Neutral — 0.6243 0.0230 0.0009 0.0060 — — 0.0074 0.0002 0.0017*Significantly higher than placebo 1 **Significantly higher than placebo1 and placebo 2

TABLE XVIII Penile Measurements (Maximum Increases Measured byRigiscan ™). Erotic Video Sequence #1 Repeated Measures Analysis ofVariance DESCRIPTIVE STATISTICS ADJUSTED (LS) MEAN ANALYSIS OF VARIANCESite Treatment N MEAN SEM LSMEAN SEM Source p-value ALL SITES Placebo #136 11.44 1.770 12.22 1.666 Treatment 0.0001 * Placebo #2 32 13.38 2.05113.65 1.714 Site 0.0264 * 4 mg 35 15.31 1.761 15.80 1.674 Treatment bySite 0.0595 6 mg 34 17.09 1.841 17.20 1.695 4 mg vs Placebo #1 0.0120 *8 mg 31 19.84 1.610 19.11 1.745 6 mg vs Placebo #1 0.0007 * SITE #1 ALLTREATMENTS 11 10.76 2.372 11.04 2.498 8 mg vs Placebo #1 0.0001 *Placebo #1 11  9.73 2.854  9.73 2.931 4 mg vs Placebo #2 0.1504 Placebo#2 10  9.00 3.300  9.21 2.996 6 mg vs Placebo #2 0.0166 * 4 mg 11  8.092.410  8.09 2.931 8 mg vs Ptacebo #2 0.0005 * 6 mg 11 10.82 3.065 10.822.931 Placebo #1 vs. #2 0.3274 8 mg  9 17.89 2.988 17.36 3.070 SITE #2ALL TREATMENTS 16 13.89 1.942 14.25 2.083 Placebo #1 16  8.94 2.233 8.94 2.430 Placebo #2 14 11.71 2.768 11.38 2.515 4 mg 15 15.27 2.37915.10 2.476 6 mg 15 17.60 2.267 17.43 2.476 8 mg 15 18.60 2.265 18.432.476 SITE #4 ALL TREATMENTS  9 21.21 3.437 21.49 2.776 Placebo #1  918.00 4.304 18.00 3.240 Placebo #2  8 21.75 4.242 20.36 3.337 4 mg  924.22 2.837 24.22 3.240 6 mg  8 24.75 3.740 23.36 3.337 8 mg  7 25.003.259 21.52 3.444

TABLE XIX Penile Measurements (Maximum Increases Measured byRigiscan ™). Neutral Video Sequence Repeated Measures Analysis ofVariance DESCRIPTIVE STATISTICS ADJUSTED (LS) MEAN ANALYSIS OF VARIANCESite Treatment N MEAN SEM LSMEAN SEM Source p-value ALL SITES Placebo #148 7.98 1.236 8.34 1.220 Treatment 0.0002 * Placebo #2 43 7.49 1.2577.65 1.272 Site 0.1092 4 mg 47 11.11 1.295 11.47 1.226 Treatment by Site0.7176 6 mg 45 12.76 1.116 13.10 1.268 4 mg vs Placebo #1 0.0230 * 8 mg41 11.98 1.366 12.40 1.331 6 mg vs Placebo #1 0.0009 * SITE #1 ALLTREATMENTS 11 10.56 1.987 10.70 1.789 8 mg vs Placebo #1 0.0060 *Placebo #1 11 8.91 2.470 8.91 2.494 4 mg vs Placebo #2 0.0074 * Placebo#2 10 5.60 2.574 5.68 2.587 6 mg vs Placebo #2 0.0002 * 4 mg 11 10.451.965 10.45 2.494 8 mg vs Placebo #2 0.0017 * 6 mg 11 12.73 2.832 12.732.494 Placebo #1 vs. #2 0.6243 8 mg  9 16.22 3.099 15.73 2.692 SITE #2ALL TREATMENTS 16 7.02 1.192 7.22 1.495 Placebo #1 16 4.44 1.554 4.442.068 Placebo #2 14 5.86 2.099 5.71 2.182 4 mg 15 8.73 2.610 8.70 2.1266 mg 15 9.60 1.514 9.56 2.126 8 mg 15 7.73 1.694 7.70 2.126 SITE #3 ALLTREATMENTS 12 12.22 1.476 12.09 1.706 Placebo #1 12 11.33 2.244 11.332.388 Placebo #2 11 10.00 1.902 10.61 2.469 4 mg 12 11.83 2.564 11.832.388 6 mg 12 13.58 1.794 13.58 2.388 8 mg 11 12.45 2.458 13.07 2.469SITE #4 ALL TREATMENTS  9 11.63 2.864 12.35 2.023 Placebo #1  9 8.674.052 8.67 2.758 Placebo #2  8 9.25 3.990 8.58 2.891 4 mg  9 14.89 3.07114.89 2.758 6 mg  7 18.14 2.747 16.51 3.046 8 mg  6 15.33 4.462 13.113.236

TABLE XX Reported Success by Tablet Strength Group 4 mg 6 mg 8 mgOverall Female 5/7 (71.4%) 11/15 (73.3%) 4/7 (57.1%) 20/29 (69.0%) Male5/7 (71.4%) 11/15 (73.3%) 4/7 (57.1%) 20/29 (69.0%)

TABLE XXI Reported Success by Apomorphine Dosage (μg/kg) Group 35-50μg/kg 50-74 μg/kg >74 μg/kg Overall Female 3/5 (60.0%) 9/11 (81.8%) 8/13(61.5%) 20/29 (69.0%) Male 4/5 (80.0%) 8/11 (72.7%) 8/13 (61.5%) 20/29(69.0%) Subject Evaluabillty Rules for Take-home Part 1. Subjects whoget one out of two successful intercourse is considered a success [basedon subject's answers to the take-home questionaaires]. 2. Subjects whotried the study medication at home, for at least two times. 3. Subjectswho attempted to try a lower or higher does if the original take-homedoes did not produce optimum results in combination with anti-nauseaagents. 4. Subjects [and partners] who filled out and returned take-homequestionnaires.

The foregoing discussion and the reported studies are intended asillustrative of the present invention and are not to be taken aslimiting. Still other variants within the spirit and scope of thisinvention are possible and will readily present themselves to thoseskilled in the art.

What is claimed is:
 1. A sublingual controlled release apomorphinedosage form that maintains circulating serum and midbrain tissue levelsof apomorphine within a range so as to induce an erection adequate forvaginal penetration but so as not to induce substantial nausea, saiddosage form containing apomorphine, mannitol, ascorbic acid, citricacid, and magnesium stearate.
 2. The dosage form in accordance withclaim 1 additionally containing a β-cyclodextrin.
 3. The dosage form inaccordance with claim 2 wherein the β-cyclodextrin ishydroxypropyl-β-cyclodextrin.